Converting enzyme inhibitors prevent the development of hypertension and normalize arterial blood pressure in spontaneously hypertensive rats (SHR), suggesting a critical role for angiotensin II (ang II) in genetic hypertension. We hypothesize that the SHR becomes hypertensive because of an enhanced slow-pressor response to ang II. This hypothesis is supported by our recent observation that SHR are remarkably more sensitive, compared to Wistar Kyoto rats (WKY), to the slow-pressor effect of exogenous ang II. Our studies also reveal that the enhanced slow-pressor response to ang II in SHR may be due to a greater effect of ang II on the kidney, adrenal medulla, or both. There are two long-term objectives of the current proposal: 1) to determine whether the enhanced slow-pressor response to ang II in spontaneously hypertensive rats (SHR) contributes to the pathophysiology of genetic hypertension, and 2) to determine whether the enhanced slow-pressor response to ang II is due to a greater direct effect of ang II on the kidney and/or the adrenal medulla. The first long-term objective will be addressed by determining whether adequate doses of the world's first in vitro selective and effective non- peptide ang II receptor antagonist (S-8303) can prevent and reverse hypertension in SHR. However, before this study can be accomplished, much in vivo pharmacology of S-8303 must be performed to determine the suitability (i.e., activity against the various biological effects of ang II, specificity, lack of intrinsic activity, and lack of non-specific effects) of S-8303 as an in vivo pharmacological probe. The second long-term objective will be addressed by determining: 1) whether ang II releases more adrenal catecholamines in SHR versus WKY, 2) whether the enhanced slow-pressor response to ang II in SHR can be prevented by removing the effects of adrenal catecholamines, and 3) whether the enhanced slow-pressor response to ang II in SHR occurs when the effects of ang II are restricted to the kidney. We think we have identified an extremely important genetic abnormality in SHR, i.e., an enhanced slow-pressor response to ang II. If this abnormality proves to be linked to the pathogenesis of genetic hypertension in SHR and if we can elucidate the mechanism of this abnormality, a significant improvement of our understanding of essential hypertension in man will be forthcoming.